Screening Derivatized Peptide Libraries for Tight Binding Inhibitors to Carbonic Anhydrase II by Electrospray Ionization-Mass Spectrometry

• Published in: Journal of medicinal chemistry 1996-05, Vol.39 (10), p.1949-1955
• Main Authors: Gao, Jinming, Cheng, Xueheng, Chen, Ruidan, Sigal, George B, Bruce, James E, Schwartz, Brenda L, Hofstadler, Steven A, Anderson, Gordon A, Smith, Richard D, Whitesides, George M
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Biological and medical sciences; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic Anhydrases - drug effects; Chemistry; Exact sciences and technology; Fourier Analysis; General pharmacology; Mass Spectrometry - methods; Medical sciences; Molecular Sequence Data; Organic chemistry; Peptides; Peptides - chemistry; Peptides - pharmacology; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; Preparations and properties
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960013g

This paper describes the use of electrospray ionization-mass spectrometry (ESI-MS) to screen two libraries of soluble compounds to search for tight binding inhibitors for carbonic anhydrase II (EC 4.2.1.1). The two libraries, H2NO2SC6H4C(O)NH-AA1-AA2-C(O)NHCH2CH2CO2H (1), where AA1 and AA2 are l-amino acids (library size:  289 compounds) or d-amino acids (256 compounds), were constructed by attaching tripeptides to the carboxyl group of 4-carboxybenzenesulfonamide. Screening of both libraries yielded, as the tightest binding inhibitor, compound 1 (AA1 = AA2 = l-Leu; binding constant K b = 1.4 × 108 M-1). The ability of ESI-MS to estimate simultaneously the relative binding affinities of a protein to soluble ligands in a library, if general, should be useful in drug development.